Tetrahydronaphthalene derivative, intermediate and application thereof

Abstract

The invention discloses a tetrahydronaphthalene derivative, an intermediate and application of the tetrahydronaphthalene derivative. The invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof. The tetrahydronaphthalene derivative or the pharmaceutically acceptable salt of the tetrahydronaphthalene derivative has a very good application prospect when being used for preparing the selective estrogen receptor medicine.

Description

[0001] This application claims priority to Chinese patent application 202410886466X, filed on July 3, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of medicinal chemistry, specifically relating to a tetrahydronaphthalene derivative, an intermediate, and its uses. Background Technology

[0003] Breast cancer is the most common type of cancer among women worldwide and the second leading cause of cancer-related death. Estrogen is considered a significant factor promoting the growth of most breast cancers. Estrogen receptor alpha-positive (ERα+) breast cancer is the most common subtype, accounting for approximately 70% of breast cancers. This type of breast cancer can be treated with endocrine blockade therapy in its early stages, but as the disease progresses, the tumor develops resistance to this therapy and accumulates numerous mutations, making treatment difficult. ESR1 mutations occur late in the treatment of advanced / metastatic breast cancer and are one of the most difficult mechanisms for acquiring resistance to treat.

[0004] Most ERα+ breast cancer patients will receive 5 years of first-line adjuvant therapy, usually in combination with CDK4 / 6 inhibitors (pembrolizumab / ribocidil / abemacebil), mTORC1 inhibitors (epirolimus), or PI3K inhibitors (abemacebil). Aromatase inhibitors (AIs) are commonly used first-line treatments in the postmenopausal period to eliminate estrogen levels by inhibiting estradiol synthesis. However, bone loss and musculoskeletal side effects reduce patient adherence. Tamoxifen is a selective estrogen receptor modulator (SERM) primarily used in premenopausal breast cancer patients in combination with ovarian suppression therapy. This SERM inhibits ERα in breast cancer cells while also acting as a partial agonist in bone and endometrium. While tamoxifen is beneficial for bone protection, its agonist activity on endometrial SERMs increases the risk of endometrial cancer and is associated with resistance mechanisms.

[0005] Elacestrant is a selective estrogen receptor modulator (SERD). Unlike modulators that inhibit estrogen activity, it dose-dependently degrades estrogen receptor α (ERα / ESR1), inhibiting estradiol-dependent ER-guided gene transcription and tumor growth, and addressing resistance caused by estrogen receptor mutations. Following FDA approval on January 27, 2023, Elacestrant (Orserdu) was included in the NCCN (2023.V2) guidelines for breast cancer on February 7, 2023, for use in postmenopausal women or adult men with ER+, HER2-, ESR1-mutant advanced or metastatic breast cancer whose disease has progressed after at least one line of endocrine therapy. This is the first oral SERD approved by the FDA. Prior to this, AstraZeneca's fulvestrant was the only approved targeted SERD, but it could only be administered via intramuscular injection. Compared to the injectable SERD fulvestrant, the successful launch of the first oral SERD elavestrant will greatly improve patient compliance due to its greater convenience, leading to better treatment outcomes and quality of life for patients.

[0006] However, from the perspective of patient medication choices or medication burden, there is still a need to develop a SERD-targeted drug with effects comparable to or better than Elacestrant. Summary of the Invention

[0007] The technical problem this invention aims to solve is to overcome the deficiency of limited types of selective estrogen receptor degrader (SERD) targeted drugs in the prior art. To this end, a tetrahydronaphthalene derivative or a pharmaceutically acceptable salt thereof is provided. The tetrahydronaphthalene derivative or its pharmaceutically acceptable salt of this invention exhibits excellent inhibitory effects on breast cancer cell growth. In particular, compared to ellastrant, some compounds of this invention possess better antitumor activity and metabolic stability, showing great promise for the preparation of drugs for treating selective estrogen receptor diseases.

[0008] This invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof.

[0009]

[0010] in,

[0011] X is -CR 1-1 R 1-2 -;

[0012] R 1-1 and R 1-2 Independently hydrogen or deuterium;

[0013] Y is -CR 2-1 R 2-2 -;

[0014] R 2-1 and R 2-2 Independently hydrogen or deuterium;

[0015] R 1 For hydrogen or

[0016] R 2 It is hydrogen, C1-C6 alkyl, and surrounded by one, two, or three Rs. c Substituted C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or with one, two, or three Rs d Substituted C1-C6 alkoxy groups;

[0017] R c and R d Deuterium is independent of other substances;

[0018] R 3 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 Aryl, "5-10-membered heteroaryl with one, two or three heteroatoms selected from N, O and S, and one, two or three heteroatoms" or "3-8-membered heterocyclic alkyl with one, two or three heteroatoms selected from N, O and S";

[0019] R 3-1 It can be hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, "a 3-8 membered heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms" or -NR a R b ;

[0020] R a and R b It is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy;

[0021] R 4 and R 5 Independently hydrogen or deuterium;

[0022] Furthermore, the compound represented by Formula I must satisfy one or more of the following conditions:

[0023] (1)R 3 for

[0024] (2)R 1 for

[0025] (3) X is -CR 1-1 R 1-2 -; where R 1-1 and R 1-2 At least one of them is deuterium;

[0026] (4)R 4 and R 5 At least one is deuterium;

[0027] (5)R 2 For 1, 2 or 3 R d Substituted C1-C6 alkoxy groups.

[0028] In certain preferred embodiments of the present invention, certain groups in the compound represented by Formula I or its pharmaceutically acceptable salt are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment").

[0029] In one embodiment, each of the C1-C6 alkyl groups and the C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably ethyl.

[0030] In one embodiment, each of the C3-C6 cycloalkyl groups is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; preferably cyclopropyl.

[0031] In one embodiment, the C1-C6 alkoxy group and the substituted C1-C6 alkoxy group are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; preferably methoxy.

[0032] In one particular scheme, R 3 In this context, the C1-C6 haloalkyl group is independently a halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, haloisobutyl, halosec-butyl, or halotert-butyl; and the halogenation is fluorinated, chlorinated, brominated, or iodinated.

[0033] In one particular scheme, R 3 In the context, the C6-C 10 The aromatic ring is a benzene ring or a naphthalene ring.

[0034] In one particular scheme, R 1-1 and R 1-2 It is hydrogen independently.

[0035] In one particular scheme, R2 It is a C1-C6 alkoxy group or surrounded by one, two or three R groups. d Substituted C1-C6 alkoxy groups; preferably C1-C6 alkoxy groups.

[0036] In one particular scheme, R 3 C1-C6 alkyl or

[0037] In one particular scheme, R 3-1 C3-C6 cycloalkyl or -NR a R b .

[0038] In one particular scheme, R a and R b It is hydrogen independently.

[0039] In one particular scheme, R 4 and R 5 It is hydrogen independently.

[0040] In one particular scheme, R 2 It is methoxy or In one particular scheme, R 3 Ethyl, In one of the solutions,

[0041] X is -CR 1-1 R 1-2 -;

[0042] R 1-1 and R 1-2 Independently hydrogen or deuterium;

[0043] Y is -CR 2-1 R 2-2 -;

[0044] R 2-1 and R 2-2 Independently hydrogen;

[0045] R 1 For hydrogen or R 2 It is a C1-C6 alkoxy group or surrounded by one, two or three R groups. d Substituted C1-C6 alkoxy groups; R 3 C1-C6 alkyl or R 3-1 C3-C6 cycloalkyl or -NR a R b ;

[0046] R a and R b Independently hydrogen;

[0047] R 4 and R 5 Independently hydrogen or deuterium;

[0048] Furthermore, the compound of formula I must satisfy one or more of the following conditions:

[0049] (1)R 3 for

[0050] (2)R 1 for

[0051] (3) X is -CR 1-1 R 1-2 -; where R 1-1 and R 1-2 At least one of them is deuterium;

[0052] (4)R 4 and R 5 At least one is deuterium;

[0053] (5)R 2 For 1, 2 or 3 R d Substituted C1-C6 alkoxy groups.

[0054] In one of the solutions,

[0055] X is -CR 1-1 R 1-2 -;

[0056] R 1-1 and R 1-2 Independently hydrogen;

[0057] Y is -CR 2-1 R 2-2 -;

[0058] R 2-1 and R 2-2 Independently hydrogen;

[0059] R 1 For hydrogen or R 2 It is a C1-C6 alkoxy group;

[0060] R 3 C1-C6 alkyl or R 3-1 C3-C6 cycloalkyl or -NR a R b ;

[0061] R a and R b Independently hydrogen;

[0062] R 4 and R 5 Independently hydrogen;

[0063] Furthermore, the compound of formula I must satisfy one or two of the following conditions:

[0064] (1)R 3 for and

[0065] (2)R 1 for In one embodiment, the compound represented by Formula I is the compound represented by Formula I-1.

[0066]

[0067] Among them, R 1 R 2 R 3 R 4 R 5 The definitions of X and Y are as described in any one of the present invention.

[0068] In one embodiment, the compound represented by Formula I has any of the following structures:

[0069]

[0070] In one embodiment, the compound represented by Formula I has any of the following structures:

[0071]

[0072] The present invention also provides the following compounds and their salts,

[0073]

[0074] Among them, R 1 R 2 R 3 R 4 and R 5 The definition is as described in any embodiment of the present invention. In one embodiment, the compound has any of the following structures:

[0075]

[0076]

[0077] The present invention also provides a pharmaceutical composition comprising:

[0078] (1) The compounds shown in Formula I above, or their pharmaceutically acceptable salts, and

[0079] (2) Pharmaceutically acceptable excipients.

[0080] The present invention also provides the use of the above-described compounds of Formula I or pharmaceutically acceptable salts thereof, the above-described pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of tumors and / or selective estrogen receptors.

[0081] In one embodiment, the tumor is breast cancer; the breast cancer may be MCF-7 breast cancer.

[0082] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0083] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, etc.

[0084] The term "halogenated alkyl" refers to a halogen-substituted alkyl group, where halogen refers to fluorine, chlorine, bromine, or iodine; and alkyl is the same as the alkyl group defined above.

[0085] The term "alkoxy" refers to the group R. X -O-, where R X It is an alkyl group as defined above.

[0086] The term "cycloalkyl" refers to a saturated monocyclic cyclic group consisting only of carbon atoms and having a specified number of carbon atoms (e.g., C3-C6). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0087] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 10 An aryl group is a cyclic group consisting solely of carbon atoms, which may be monocyclic or polycyclic, and at least one ring is aromatic (conforming to Hückel's rule). An aryl group is linked to other segments of the molecule via an aromatic or non-aromatic ring. Aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0088] The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably containing one, two, or three independent 5-10 membered aromatic monocyclic or polycyclic rings selected from nitrogen, oxygen, and sulfur, with at least one ring being aromatic (conforming to Hückel's rule). The heteroaryl group is linked to other segments of the molecule through an aromatic or non-aromatic ring. Heteroaryl groups include, but are not limited to, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, thiophene, isoxazolyl, oxazolyl, diazolyl, imidazole, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.

[0089] The term "heterocyclic alkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3-8), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which can be monocyclic, bridged, or spirocyclic, and each ring is saturated. A bridged ring is a polycyclic ring that shares two or more atoms between monocyclic rings. A spirocyclic ring is a polycyclic ring that shares one atom between monocyclic rings. Heterocyclic alkyl groups include, but are not limited to, nitrogen-containing heterocyclic butyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, and piperidinyl.

[0090] The term "tumor" is a general term for a group of diseases that can affect any part of the body. A defining characteristic is the rapid generation of abnormal cells that grow beyond their normal boundaries, invading adjacent parts of the body and spreading to other organs—a process known as metastasis. Examples include breast cancer, stomach cancer, lymphoma, and ovarian cancer.

[0091] The term "salt" includes "salts formed with organic or inorganic acids" and "salts formed with organic or inorganic bases".

[0092] The term "pharmaceuticalally acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.

[0093] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, intended for administration to mammals, such as humans, in need of such treatment.

[0094] The term "pharmaceuticalally acceptable excipient" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative excipients include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals.

[0095] The term “treatment” refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that triggers the disease; or (3) slowing the development of one or more biological manifestations of a disease.

[0096] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0097] The reagents and raw materials used in this invention are all commercially available.

[0098] The positive and progressive effects of this invention are as follows: the tetrahydronaphthalene derivative of this invention has a good inhibitory effect on breast cancer growth, and compared with ellastrant, some compounds of this invention have better anti-tumor activity and metabolic stability, and have very good prospects for use in the preparation of drugs for treating selective estrogen receptors. Attached Figure Description

[0099] Figure 1 Results of the effects of compounds on animal body weight;

[0100] Figure 2 Results of the compound's inhibitory effect on tumor growth. Detailed Implementation

[0101] Example 1: Synthesis of N-(5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)phenyl)acetamide (IIa)

[0102]

[0103] Step 1: 7,8-Dihydro-2-naphthol (IIa-1)

[0104] 30.0 g (184.97 mmol) of 6-hydroxy-3,4-dihydronaphthyl-1(2H)-one was dissolved in 400 mL of methanol and cooled to 0 °C. Sodium borohydride (NaBH4, 14.0 g, 369.94 mmol) was added in portions, and the mixture was stirred at 0 °C for 2 hours until complete. The reaction was quenched with water, concentrated to dryness under reduced pressure, and the residue was redissolved in toluene (450 mL). p-Toluenesulfonic acid (1.59 g, 9.25 mmol) was added, and the mixture was refluxed under nitrogen protection for approximately 1 hour. The mixture was cooled to room temperature (25-30 °C), and the reaction mixture was washed with saturated sodium bicarbonate (NaHCO3) solution, water, and brine. The organic layer was dried over anhydrous sodium sulfate (Na2SO4). The residue was purified by silica gel chromatography to give compound IIa-1 (21.52 g). MS (ESI, m / z): 147 [M+H] + .

[0105] Step 2: 7-(methoxymethoxy)-1,2-dihydronaphthalene (IIa-2)

[0106] Under nitrogen protection, compound IIa-1 (20.0 g, 136.81 mmol) and diisopropylethylamine (35.36 g, 273.62 mmol) were dissolved in N,N-dimethylformamide (200 mL) solution, followed by dropwise addition of a tetrahydrofuran (30 mL) solution of bromo(methoxy)methane (MOMBr, 18.81 g, 136.81 mmol), and the reaction mixture was stirred for 16 hours. The reaction mixture was poured into ice water (300 mL), extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium carbonate solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography to give compound IIa-2 (23.76 g). MS (ESI, m / z): 191 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ6.96(d,1H),6.79(d,2H),6.42(dt,1H),5.90(dt,1H),5.16(s,2H),3.37(s,3H),2.69(t,2H),2.21(tdd,2H).

[0107] Step 3: 2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclo(IIa-3)

[0108] Under nitrogen protection, compound IIa-2 (15.0 g, 78.85 mmol) and 4,4,4',4',5,5,5',5'-octylmethyl-2,2'-bi(1,3,2-dioxaborhexane) (60.07 g, 236.54 mmol) were dissolved in a mixed solvent of anhydrous tetrahydrofuran (300 mL) and tert-butanol (11.69 g, 157.69 mmol). Potassium tert-butoxide (17.7 g, 157.69 mmol) and ferrous chloride (500 mg, 3.94 mmol) were added, and the mixture was refluxed for 24 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth and evaporated to dryness. The residue was purified by silica gel chromatography to give the target compound IIa-3 (22.81 g). MS (ESI, m / z): 319 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ6.94(d,1H),6.74-6.65(m,2H),5.10(s,2H),3.34(s ,3H),2.74-2.52(m,4H),1.90-1.81(m,1H),1.57-1.45(m,1H),1.18(d,13H).

[0109] Step 4: 2-(4-methoxy-2-nitrophenyl)-6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthalene (IIa-4)

[0110] Under nitrogen protection, compound IIa-3 (10.0 g, 31.42 mmol), 1-bromo-4-methoxy-2-nitrobenzene (7.29 g, 31.42 mmol), palladium acetate (353 mg, 1.57 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolide hydrochloride (674 mg, 1.57 mmol), and cesium fluoride (11.93 g, 78.56 mmol) were dissolved in toluene (100 mL), and the mixture was refluxed for 24 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the target compound IIa-4 (5.84 g). MS (ESI, m / z): 344 [M+H] + ;

[0111] Step 5: 5-Methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphth-2-yl)aniline (IIa-5)

[0112] Compound IIa-4 (5.0 g, 14.56 mmol) was dissolved in a mixed solvent of tetrahydrofuran (50 mL) and isopropanol (50 mL), and reacted at room temperature for 10 h under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, the residue was washed with isopropanol, and the filtrate was concentrated under reduced pressure to give the target compound IIa-5 (4.32 g). MS (ESI, m / z): 314 [M+H] + ;

[0113] Step 6: N-(5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphth-2-yl)phenyl)acetamide (IIa)

[0114] A tetrahydrofuran solution of acetaldehyde (6.4 mL, 12.76 mmol, 2 M), compound IIa-5 (4.0 g, 12.76 mmol), and acetic acid (766 mg, 12.76 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL), and stirred at room temperature for 3 hours. Sodium triacetate borohydride (NaBH(OAc)3, 5.4 g, 25.53 mmol) was then added to the mixture. Stirring was continued at room temperature for another 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (150 mL). The reaction mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate. The reaction mixture was filtered. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound IIa (3.86 g). MS (ESI, m / z): 342 (M+H)+ ; 1 H NMR(400MHz,Chloroform-d)δ7.03(dd,2H),6.83(dd,2H),6.30-6.23(m,2H),5.16(s,2H),3.80(s,3H),3.64(d,1 H),3.49(s,3H),3.17(qd,2H),3.04-2.92(m,3H),2.76(s,2H),2.13-2.03(m,1H),2.03-1.87(m,1H),1.27(t,3H).

[0115] Example 2: Synthesis of N-ethyl-5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)aniline (IIb)

[0116]

[0117] Step 1: N-(5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphth-2-yl)phenyl)acetamide (IIa)

[0118] Compound IIa-5 (6.0 g, 19.15 mmol) and triethylamine (2.9 g, 28.72 mmol) were dissolved in anhydrous tetrahydrofuran (50 mL), and then acetic anhydride (2.4 g, 22.97 mmol) was added to the mixture. The mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched with ammonia, diluted with water, and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate. The reaction mixture was filtered. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound IIa (6.5 g). MS (ESI, m / z): 356 [M+H] + ; 1 H NMR(400MHz,Chloroform-d)δ7.33(d,1H),7.19(d,1H),7.01(d,2H),6.84(dt,2H),6.78(dd,1H),5.17(s,2H),3.8 1(s,3H),3.50(s,3H),2.94(dd,2H),2.89(d,1H),2.80(d,1H),2.17(s,3H),2.08-2.02(m,1H),2.00-1.81(m,2H).

[0119] Step 2: N-(ethyl-1,1-d2)-5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)aniline (IIb)

[0120] Compound IIa (5.0 g, 14.07 mmol) was dissolved in tetrahydrofuran (45 mL), cooled to 0 °C, and then lithium deuterated aluminum hydride (1.2 g, 28.13 mmol) was slowly added dropwise. The reaction was stirred at 65 °C for 3 hours. The reaction was monitored by TLC until complete, the reaction was quenched with water, diluted with ethyl acetate, sodium sulfate was added, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound IIb (3.8 g). MS (ESI, m / z): 344 [M+H] + ; 1 H NMR(400MHz,Chloroform-d)δ7.02(dd,2H),6.82(dd,2H),6.29-6.22(m,2H),5.15(s,2H),3.79(s,3H),3. 63(d,1H),3.48(s,3H),3.03-2.91(m,3H),2.75(s,2H),2.12-2.02(m,1H),2.02-1.86(m,1H),1.25(t,3H).

[0121] Example 3: Synthesis of N-ethyl-5-(methoxy-d3)-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)aniline (IIc)

[0122]

[0123] Step 1: 1-Bromo-4-methoxy-d3-2-nitrobenzene (IIc-1)

[0124] 4-Bromo-3-nitrophenol (20.0 g, 91.74 mmol) and sodium carbonate (14.6 g, 137.61 mmol) were dissolved in N,N-dimethylformamide (200 mL), and deuterated iodomethane (14.6 g, 100.91 mmol) was added. The reaction was carried out at 30 °C for 12 hours, and the reaction was monitored by LC-MS until complete. The mixture was filtered, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give the target product (19.56 g). MS (ESI, m / z) 235 & 237 [M+H] + .

[0125] Step 2: 2-(4-(methoxy-d3)-2-nitrophenyl)-6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthalene (IIc-2)

[0126] Under nitrogen protection, compounds IIa-3 (20.0 g, 62.85 mmol), IIc-1 (14.77 g, 62.85 mmol), palladium acetate (706 mg, 3.14 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium hydrochloride (1.35 g, 3.14 mmol), and cesium fluoride (23.87 g, 157.12 mmol) were dissolved in toluene (300 mL), and the mixture was refluxed for 24 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give the target compound IIc-2 (6.83 g). MS (ESI, m / z): 347 [M+H] + ;

[0127] Step 3: 5-(methoxy-d3)-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)aniline (IIc-3)

[0128] Compound IIc-2 (6.0 g, 17.32 mmol) and palladium on carbon (10% wt, 1.47 g, 1.39 mmol) were dissolved in a mixed solvent of tetrahydrofuran (30 mL) and isopropanol (30 mL), and reacted at room temperature for 10 h under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, the residue was washed with isopropanol, and the filtrate was concentrated under reduced pressure to give the target compound IIc-3 (5.16 g). MS (ESI, m / z): 317 [M+H] + ;

[0129] Step 4: N-Ethyl-5-(methoxy-d3)-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)aniline (IIc)

[0130] Compound IIc-3 (5.0 g, 15.80 mmol) was dissolved in acetaldehyde tetrahydrofuran solution (5 M, 3.16 mL, 15.80 mmol) in anhydrous methanol (50 mL). The reaction was carried out at room temperature for 6 hours. Then, sodium borohydride (1.2 g, 31.60 mmol) was added in portions, and the reaction was continued at room temperature for 2 hours. The reaction was quenched with water, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound IIc (4.85 g). MS (ESI, m / z): 345 [M+H] + ;

[0131] Example 4: Synthesis of 6-(2-(ethyl(4-(2-(ethylamino)ethyl-2,2-d2)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I-1)

[0132]

[0133] Step 1: N-Ethyl-2-(4-((Ethyl(5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)phenyl)amino)methyl)phenyl)acetamide (I-1-1)

[0134] Compound IIa (5.0 g, 14.64 mmol), N-ethyl-2-(4-formylphenyl)acetamide (2.8 g, 14.64 mmol), and acetic acid (880 mg, 14.64 mmol) were dissolved in anhydrous tetrahydrofuran (55 mL) and stirred at room temperature for 3 hours. Sodium triacetate borohydride (NaBH(OAc)3, 6.2 g, 29.29 mmol) was then added to the mixture. Stirring was continued at room temperature for another 3 hours. The reaction mixture was quenched with a saturated sodium bicarbonate solution (150 mL). The reaction mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate. The reaction mixture was filtered. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound I-1-1 (6.92 g). MS (ESI, m / z): 517 (M+H) + ;

[0135] Step 2: 6-(2-(ethyl(4-(2-(ethylamino)ethyl-2,2-d2)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I-1)

[0136] Under nitrogen protection, lithium aluminum deuteride (LiAlD4, 0.315 g, 7.51 mmol) was suspended in anhydrous tetrahydrofuran (12 mL). The solution was cooled to 0–5 °C, and a solution of compound I-1-1 (2.0 g, 3.75 mmol) in anhydrous tetrahydrofuran (3 mL) was slowly added dropwise through a dropping funnel over 30 minutes. The mixture was then stirred for another 30 minutes, followed by reflux for 30 minutes. After cooling to room temperature, the solution was quenched with saturated ammonium chloride aqueous solution (2 mL), and then anhydrous magnesium sulfate was added. The mixture was stirred for 30 minutes, filtered, and concentrated. The residue was then added to dilute hydrochloric acid and stirred for 1 hour. The residue was neutralized with sodium bicarbonate, extracted with dichloromethane, dried, concentrated under reduced pressure, and the crude product was purified by reversed-phase chromatography to obtain compound I-1 (1.28 g). MS (ESI, m / z): 461 [M+H] + ; 1H NMR(400MHz, Methanol-d4)δ8.54(s,1H),7.24(d,2H),7.16-7.09(m,3H),6.84-6.77(m,2H),6.68(dd,1H),6.53(dd,2H),4.01(s,2H),3.76(s ,3H),3.70-3.55(m,1H),3.02(q,2H),2.94(q,2H),2.89(s,2H),2.83- 2.76(m,2H),2.61(d,2H),1.82-1.63(m,2H),1.27(t,3H),0.95(t,3H).

[0137] Example 5: Synthesis of 6-(2-(ethyl-1,1-d2)(4-(2-(ethylamino)ethyl-2,2-d2)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I-2)

[0138]

[0139] Step 1: N-ethyl-2-(4-(((ethyl-1,1-d2)(5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)phenyl)amino)methyl)phenyl)acetamide (I-2-1)

[0140] Compound IIb (5.0 g, 14.56 mmol), N-ethyl-2-(4-formylphenyl)acetamide (2.78 g, 14.56 mmol), and acetic acid (874 mg, 14.56 mmol) were dissolved in anhydrous tetrahydrofuran (55 mL) and stirred at room temperature for 3 hours. Sodium triacetate borohydride (NaBH(OAc)3, 6.17 g, 29.12 mmol) was then added to the mixture. Stirring was continued at room temperature for another 3 hours. The reaction mixture was quenched with a saturated sodium bicarbonate solution (150 mL). The reaction mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate. The reaction mixture was filtered. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound I-2-1 (6.5 g). MS (ESI, m / z): 519 [M+H] + ;

[0141] Step 2: Synthesis of 6-(2-((ethyl-1,1-d2)(4-(2-(ethylamino)ethyl-2,2-d2)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I-2)

[0142] Under nitrogen protection, lithium aluminum deuteride (LiAlD4, 0.153 g, 3.66 mmol) was suspended in anhydrous tetrahydrofuran (12 mL). The solution was cooled to 0-5 °C, and anhydrous tetrahydrofuran (3 mL) containing compound I-2-1 (1.0 g, 1.83 mmol) was slowly added dropwise through a dropping funnel over 30 min. The mixture was stirred for another 30 min, then refluxed for 30 min. After cooling to room temperature, 2 mL of saturated ammonium chloride solution was added to quench the reaction, followed by the addition of anhydrous magnesium sulfate. The mixture was stirred for 30 min, filtered, and concentrated. The residue was then added to dilute hydrochloric acid and stirred for 1 hour. The mixture was neutralized with sodium bicarbonate, extracted with dichloromethane, concentrated under reduced pressure, and purified by reversed-phase chromatography followed by silica gel column chromatography to obtain compound I-2 (0.756 g). MS (ESI, m / z): 463 [M+H] + ; 1 H NMR(400MHz, Methanol-d4)δ8.54(s,1H),7.23(d,2H),7.15-7.09(m,3H),6.83-6.77(m,2H),6.68(dd,1H),6.57-6.50(m,2H),4.01(s, 2H),3.75(s,4H),3.64(dtd,1H),3.00(q,2H),2.89(s,2H),2.84-2.76(m,2H),2.61(d,2H),1.72(dddd,3H),1.26(t,3H),0.93(s,3H).

[0143] Example 6 Synthesis of 6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-(methoxy-d3)phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I-3)

[0144]

[0145] Step 1: N-Ethyl-2-(4-((Ethyl(5-(methoxy-d3)-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)phenyl)amino)methyl)phenyl)acetamide (I-3-1)

[0146] Compound IIc (4.5 g, 13.06 mmol), N-ethyl-2-(4-formylphenyl)acetamide (2.5 g, 13.06 mmol), and acetic acid (784 mg, 13.06 mmol) were dissolved in anhydrous tetrahydrofuran (55 mL) and stirred at room temperature for 3 hours. Sodium triacetate borohydride (NaBH(OAc)3, 5.5 g, 26.13 mmol) was then added to the mixture. Stirring was continued at room temperature for another 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (150 mL). The reaction mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate. The reaction mixture was filtered. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound I-3-1 (6.1 g). MS (ESI, m / z): 520 [M+H] + ;

[0147] Step 2: 6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-(methoxy-d3)phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I-3)

[0148] Under a nitrogen atmosphere, compound I-3-1 (6.0 g, 11.55 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), cooled to 0 °C, and a borane tetrahydrofuran solution (23.1 mL, 23.1 mmol, 1 M) was slowly added dropwise. The mixture was then heated to room temperature and stirred for 8 hours. The reaction was monitored by TLC until complete. The solution was poured into ice-cold dilute hydrochloric acid and stirred for 30 minutes. The mixture was neutralized with sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography to give compound I-3 (4.93 g). MS (ESI, m / z): 462 [M+H] + ; 1 H NMR(400MHz, Methanol-d4)δ8.64(s,1H),7.23(d,2H),7.12(d,3H),6.83–6.76(m,2H),6.68(dd,1H),6.60–6.45(m,2H),4.00(s,2H) ,3.63(ddt,1H),3.12(t,2H),3.00(q,2H),2.91(dt,4H),2.84–2.75(m,2H),2.60(d,2H),1.71(dddt,2H),1.26(t,3H),0.95(t,3H).

[0149] Example 7: Synthesis of 6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-yl dihydrophosphate (I-5)

[0150]

[0151] Step 1: Tert-butyl ethyl (4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)tert-butyl carbamate (I-5-1)

[0152] Compound I-4 (3.0 g, 6.54 mmol) was dissolved in ethanol (40 mL), and then di-tert-butyl dicarbonate (1.43 g, 6.54 mmol) was added. The mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography to give compound I-5-1 (3.5 g). MS (ESI, m / z): 559 [M+H] + ;

[0153] Step 2: Tert-butyl (4-(((2-(6-((di-tert-butoxyphosphono)-1,2,3,4-tetrahydronaphthyl-2-yl)-5-methoxyphenyl)(ethyl)amino)methyl)phenethyl)(ethyl)carbamate tert-butyl ester (I-5-2)

[0154] Compound I-5-1 (2.0 g, 3.58 mmol), N,N-dimethylpyridin-4-amine (44 mg, 357.93 μmol), and carbon tetrachloride (2.75 g, 17.90 mmol) were dissolved in N,N-dimethylformamide (8 mL), and di-tert-butylphosphonite (1.04 g, 5.37 mmol) was added. The mixture was stirred at 25 °C for 24 hours under nitrogen protection. The reaction solution was poured into ice water and extracted with dichloromethane. The combined organic phases were washed with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound I-5-2 (1.14 g). MS (ESI, m / z): 751 [M+H] + ;

[0155] Step 3: 6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-yl dihydrophosphate (I-5)

[0156] Compound I-5-2 (1.14 g, 1.52 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of dioxane (4 M, 5 mL) solution. The mixture was stirred at room temperature for 3 hours. Thin-layer chromatography (TLC) showed complete consumption of the starting material. The solution was concentrated to dryness under reduced pressure, stirred with diethyl ether for 1 hour, filtered, and dried to give compound I-5 (0.55 g). MS (ESI, m / z): 539 [M+H] + ; 1HNMR(400MHz,Methanol-d4)δ8.09(s,1H),7.22(d,2H),7.12(d,1H),7.05(d,2H),6.93(d,2H),6.87(d,1H),6.82(d,1H),6.69(dd,1H),4.04–3 .95(m,2H),3.78(s,3H),3.43(s,1H),3.03(p,6H),2.86(dd,2H),2.78– 2.69(m,2H),2.56(d,2H),1.73–1.62(m,2H),1.30(t,3H),0.96(t,3H).

[0157] Example 8: Synthesis of N-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)cyclopropaneformamidin (I-6)

[0158]

[0159] Step 1: (4-((ethyl(5-methoxy-2-(6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)phenyl)amino)methyl)phenethyl)tert-butyl carbamate (I-6-1)

[0160] Compound IIb (10.0 g, 29.29 mmol), tert-butyl (4-formylphenylethyl)carbamate (7.3 g, 29.29 mmol), and acetic acid (1.8 g, 29.29 mmol) were dissolved in anhydrous tetrahydrofuran (110 mL) and stirred at room temperature for 3 hours. Sodium triacetate borohydride (NaBH(OAc)3, 12.4 g, 58.57 mmol) was then added to the mixture. Stirring was continued at room temperature for another 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (300 mL). The reaction mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate. The reaction mixture was filtered. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound I-6-1 (15.36 g). MS (ESI, m / z): 575 [M+H] + ;

[0161] Step 2: 6-(2-((4-(2-aminoethyl)benzyl)(ethyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (I-6-2)

[0162] Compound I-6-1 (13.0 g, 22.62 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of dioxane (4 M, 8 mL) solution, and stirred at room temperature for 3 hours. Thin-layer chromatography (TLC) showed complete consumption of the starting material. The solution was concentrated to dryness under reduced pressure, stirred with diethyl ether for 1 hour, filtered, and dried to give compound I-6-2 (10.5 g). MS (ESI, m / z): 431 [M+H] + ;

[0163] Step 3: N-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)cyclopropaneformamidin(I-6)

[0164] Under nitrogen protection, cyclopropylformamidin hydrochloride (2.6 g, 21.54 mmol) and sodium ethoxide (2.69 g, 39.48 mmol) were dissolved in anhydrous ethanol (75 mL), and the mixture was stirred at room temperature for 30 minutes. Then, compound I-6-2 (8.5 g, 17.95 mmol) was added, and the mixture was heated to 40 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. The mixture was neutralized with sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound I-6 (6.52 g). MS (ESI, m / z): 498 [M+H] + ; 1 H NMR(400MHz,Methanol-d4)δ8.51(s,1H),7.23(d,2H),7.12(dd,3H),6.83– 6.79(m,2H),6.68(dd,1H),6.54(dt,2H),4.01(s,2H),3.76(s,3H),3.69–3. 63(m,1H),3.47(t,2H),2.93(q,2H),2.87(t,2H),2.78-2.83(m,2H),2.63(d ,2H),1.70-1.81(m,3H),1.16–1.06(m,2H),1.01–0.98(m,2H),0.95(t,3H).

[0165] Example 9: Synthesis of 1-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)-5-methoxyphenyl)aminomethyl)phenethyl)guanidine (I-7)

[0166]

[0167] Under nitrogen protection, compound I-6-2 (5.5 g, 11.61 mmol) and 1H-pyrazole-1-formamidin hydrochloride (1.37 g, 23.23 mmol) were dissolved in ethanol (55 mL), and the mixture was heated to 90 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. The mixture was neutralized with sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound I-7 (3.57 g). MS (ESI, m / z): 473 [M+H] + ; 1 H NMR(400MHz, Methanol-d4)δ8.53(s,1H),7.21(d,2H),7.12(t,3H),6.81(q,2H),6.68(dd,1H),6.56–6.50(m,2H),4.00(s,2H),3 .76(s,3H),3.66(d,1H),3.40(t,2H),2.93(q,2H),2.85–2.78(m,4H),2.61(d,2H),1.75(dd,1H),1.64-169(m,1H),0.94(t,3H).

[0168] Example 1: Evaluation of the anti-breast cancer cell proliferation activity of the compounds in this invention.

[0169] 1) Cell culture and proliferation assay

[0170] All cells were cultured in a 37°C, 5% CO2 incubator using Dulbecco modified Hawkwhale medium containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. MCF-7 breast cancer cells were pretreated with phenol red-free RPMI-1640 medium containing 10% activated charcoal and dextran-treated FBS, 1% antibiotic-antifungal agent, and 1% maximum dose of glutamine at 37°C and 5% CO2.

[0171] 2) Cell viability was assessed using the MTT assay.

[0172] MCF-7 breast cancer cells were de-estrogenized two days prior to culture. The culture medium was replaced with phenol red-free RPMI-1640 and estrogen-de-estrogen-treated FBS. MCF-7 cells were seeded into 96-well plates (1000-2000 cells per well) and attached overnight. All compounds were dissolved in dimethyl sulfoxide (DMSO). Control cells were treated with 0.1% DMSO and incubated for 96-120 hours. MTT (5%, 5 mg / mL, dissolved in phosphate-buffered saline [PBS]) was added to the wells and incubated for approximately 4 hours. Subsequently, the waste solution was discarded, and 200 μL of DMSO was added, followed by shaking on a shaker for approximately 10 minutes. Finally, absorbance was measured at 490 nm. Growth inhibition rate was calculated as (Ac-As) / (Ac-Ab) × 100%, where Ac, As, and Ab represent the absorbance of the control, sample, and blank wells, respectively. The EC50 of the compounds was calculated using Excel. 50 value

[0173] Example 2: Comparative in vivo pharmacokinetic study of some of the compounds in this invention with elascerant.

[0174] 1. Test compound

[0175] Compound of the present invention: I-5;

[0176] Reference compound: Elasistrant, CAS No.: 722533-56-4.

[0177] 2. Preparation of test sample

[0178] Table 1 ： Sample configuration information

[0179]

[0180] 3. Laboratory animals

[0181] Species: Healthy male SD rats (SPF grade), weighing 280–300g.

[0182] Source: Provided by Shanghai Sixin Pharmaceutical Technology Co., Ltd.

[0183] Number: 9 males; Animal selection: randomly grouped into groups of 3.

[0184] 4. Administration method and blood collection time

[0185] Weigh the patient before administration and calculate the dosage based on their body weight. Administer via intravenous injection.

[0186] Following intravenous administration (2 mg / kg), blood was collected from rats via vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration. The blood was anticoagulated with EDTA-K2 and placed on ice after collection.

[0187] After oral administration (10 mg / kg, 12 mg / kg), blood was collected from rat veins at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration. The blood was anticoagulated with EDTA-K2 and placed on ice after collection.

[0188] 5. Sample processing steps

[0189] 1) Sample preparation:

[0190] Take 10 μL of plasma sample and mix it with 90 μL of (acetonitrile:methanol = 1:1) containing 20 ng / mL of internal standard (IS).

[0191] 2) Protein precipitation:

[0192] Mix the mixture in a vortex mixer for 5 minutes, then centrifuge at 4000 rpm for 15 minutes.

[0193] 3) Transfer of supernatant:

[0194] Transfer 50 μL of the supernatant and mix it with 50 μL of water.

[0195] 4) Analysis:

[0196] The mixture was injected into LC-MS / MS for analysis.

[0197] 6. Data Processing

[0198] Pharmacokinetic parameters were calculated using non-compartmental models in Phoenix WinNonlin 7.0 software based on blood drug concentration data at different time points, providing exposure (AUC) and half-life (T). 1 / 2 The parameters included metabolic clearance rate (Cl) and mean residence time (MRT). The results are shown in Table 2 below.

[0199] Table 2 ： Pharmacokinetic parameters of the compound in SD rats

[0200]

[0201]

[0202] Note: *I-5 is the prodrug of the control compound Elacestrant. Pharmacokinetic parameters in SD rats were calculated based on Elacestrant.

[0203] * *Based on the same molar amount of the control compound Elacestrant (10 mg / kg orally), the oral dose of I-5 is converted to 12 mg / kg.

[0204] Experimental results showed that, when administered orally, I-5, compared to the control compound (Elacestrant), had a lower T... max The duration of absorption was 4 hours, indicating that the prodrug conversion process did not significantly delay the absorption rate. From a systemic exposure perspective, the C-value of Elacestrant, converted from oral I-5, was [not specified]. max The concentration of oral I-5 was 57.2 ng / mL, approximately 35% higher than that of direct oral Elacestrant (42.3 ng / mL); the oral I-5 exposure (AUC) was 532 h·ng / mL, slightly higher than that of direct oral Elacestrant (513 h·ng / mL), indicating slightly better overall exposure. Regarding half-life and residence time, the oral I-5 half-life (T5) was... 1 / 2 The mean residence time (MRT) of I-5 was 4.23 h, slightly better than that of oral Elacestrant (3.86 h), and both remained around 7 h, indicating that the elimination kinetics of the prodrug after conversion were basically consistent. Regarding bioavailability (F%), compared with intravenous Elacestrant data, the F% of oral I-5 was 25.8%, comparable to the 24.9% of direct oral Elacestrant. In summary, I-5 can be rapidly converted to the active drug Elacestrant after oral administration, and in rats, it exhibits similar or slightly better peak plasma concentration, overall exposure, and half-life than direct oral Elacestrant, while maintaining comparable bioavailability. These results support I-5 as an effective prodrug candidate for Elacestrant.

[0205] Example 3: Comparative in vivo pharmacodynamic study of some of the compounds in this invention with elascerant.

[0206] 1. Purpose

[0207] The efficacy of some of the compounds in the embodiments of the present invention was studied in the MCF-7 model.

[0208] 2.1. Test Compound

[0209] Compounds of the present invention: I-5, I-6, I-7;

[0210] Reference compound: Elacestrant.

[0211] 3. Instruments and equipment used in the experiment

[0212] Table 3： Instrument and Equipment List

[0213]

[0214]

[0215] 4. Laboratory animals

[0216] Female NOG mice (purchased from: Beijing Vital River Laboratory Animal Technology Co., Ltd.), age: 6-8 weeks; quantity: 30 mice.

[0217] 5. Preparation of the drug delivery solution

[0218] Table 4 ： Preparation of compound drug delivery solutions

[0219]

[0220] 6. Experimental Methods

[0221] 6.1 Culture of MCF-7 cells

[0222] MCF-7 cells (human breast cancer cell line, provided by Sixin Cell Bank) were cultured in vitro in Leibovitz's medium supplemented with 10% FBS and 1% PS (37°C, 0% CO2), and passaged 2-3 times per week. Cells in the exponential growth phase were collected and resuspended in a suspension of PBS and Matrigel (PBS to Matrigel volume ratio 1:1) to obtain a cell concentration of 5.0 × 10⁻⁶ cells / year. 7 A cell suspension of 1 / mL was used to inoculate mice.

[0223] 6.2 Cell Seeding

[0224] On the day of tumor cell inoculation, a 60-day sustained-release 17β-estradiol tablet (0.72 mg, Innovative Research of America) was subcutaneously implanted. The next day, 1.5 × 10⁻⁶ tablets were administered. 7 MCF-7 cells were mixed with Matrigel and then subcutaneously injected into nude mice on the opposite back.

[0225] 6.3 Grouping and Dosing

[0226] Six days after cell injection, the tumor volume of 30 mice was measured, with a tumor volume of approximately 150 mm². 3 Twenty mice were randomly divided into five groups of four for the efficacy experiment. The day of administration was defined as Day 0. The specific group information and administration information are shown in Table 5 below.

[0227] Table 5： Experimental Groups

[0228]

[0229]

[0230] Note: *Dosage volume: Adjust the dosage according to body weight 10 mL / kg. If the mouse's body weight drops by more than 15%, discontinue the drug or reduce the dosage. Resume the drug when the body weight drops back to within 10%.

[0231] 6.4 Tumor Measurement

[0232] The tumor size was measured using vernier calipers twice a week, with tumor volume expressed in mm. 3 The formula for calculating tumor volume is: V = 0.5 × a × b 2 Where a and b are the long and short diameters of the tumor, respectively. The tumor size is then used to calculate the relative tumor growth rate (T / C%). The T / C% value is calculated using the formula: T / C% = (T... i -T0) / (V i -V0)×100%, T i V is the average tumor volume of the treatment group on a certain day, T0 is the average tumor volume of the treatment group on the first day of treatment (before drug administration), and V is the average tumor volume of the treatment group on the first day of treatment. i To measure T i The average tumor volume of the control group on that day, V0 is the average tumor volume of the control group on the first day of treatment.

[0233] Calculate the TGI (%) for each group using the formula: Tumor Growth Inhibition Rate (TGI) (%) = 100% - T / C (%).

[0234] 7. Statistical Analysis

[0235] Experimental data are presented as mean and standard error (SEM), including tumor volume and mouse weight at each time point. All data were statistically analyzed using GraphPad Prism8. One-way ANOVA was used for intergroup comparisons, with p < 0.05 indicating statistical significance.

[0236] 8. Test Results

[0237] 8.1 Effects on body weight

[0238] The effects of drug treatment on animal body weight during administration are shown in Table 6. Figure 1 .

[0239] Table 6. Effects of the test substances on animal body weight in the MCF-7 xenograft tumor model.

[0240]

[0241]

[0242] Note: **P < 0.01 vs G1 group;

[0243] Results of the effects of the test substance on animal body weight (Table 6 and Figure 1 The results showed that, compared with the solvent control group, the I-5 (G2) group had almost no weight loss, and its safety was comparable to that of the solvent control, exhibiting the best tolerability and safety among all tested compounds. In contrast, the Elacestrant group showed significant toxic side effects at a dose of 30 mpk, with a weight loss rate exceeding 15% on days 0-3. After 3 days of drug withdrawal, the dose was reduced to 15 mpk, resulting in a 7.1% weight loss at the experimental endpoint (one mouse discontinued treatment after 26 days due to a weight loss exceeding 20%), demonstrating significant systemic toxicity compared to the solvent control group (P < 0.01). At an equivalent dose to Elacestrant (G5 group), the I-5 (G2 group) showed good weight tolerability, indicating that prodrug design can effectively reduce the original systemic toxicity of the parent drug Elacestrant.

[0244] 7.2 Tumor growth inhibition results

[0245] Table 7 shows the tumor growth curves and tumor weight results for each group of animals in this experiment. Figure 2 .

[0246] Table 7. Antitumor activity of the test substances in the MCF-7 xenograft tumor model

[0247]

[0248] Note: **P<0.01, ***P<0.001, vs group G1;

[0249] Results of the test drugs' inhibitory effects on tumor growth (Table 7 and) Figure 2 The results showed that after 35 days of administration, the tumor volumes in the solvent control group, I-5 group, I-7 group, I-6 group, and the control compound Elacestrant group were 1890.58±200.86 mm. 3 1189.13±313.95mm 3 1365.22±182.41 mm 3 1777.45±38.87mm 3 and 1137.50±179.99mm 3Compared with the control group, except for the I-6 (G4) group, the tumor volume of all other groups was significantly reduced (P<0.01, P<0.001), and the tumor growth inhibition rate (%TGI) was 40.3%, 30.2%, and 43.3%, respectively. Compared with the Elacestrant group, I-5 had comparable efficacy.

[0250] In summary, I-5 achieves efficacy comparable to Elacestrant while offering a significantly reduced systemic toxicity and thus a superior safety profile compared to Elacestrant.

[0251] In vivo pharmacokinetic (PK) studies and in vivo pharmacodynamic studies have shown that some compounds I-5 of the present invention exhibit superior pharmacokinetic characteristics compared to Elacestrant, demonstrating equivalent antitumor activity to Elacestrant at equivalent doses, while also showing significantly better in vivo safety than Elacestrant. Therefore, some compounds of the present invention show great promise for the development of therapeutic drugs targeting selective estrogen receptors.

[0252] The above embodiments of the present invention are merely examples for clearly illustrating the present invention and are not intended to limit the implementation of the present invention. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively describe all possible implementations here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein, X is -CR 1-1 R 1-2 -; R 1-1 and R 1-2 are independently hydrogen or deuterium; Y is -CR 2-1 R 2-2 -; R 2-1 and R 2-2 are independently hydrogen or deuterium; R 1 is hydrogen or R 2 hydrogen, Ci-C6-alkyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, C1-C6- alkoxy or Ci-C6-haloalkoxy; c substituted by 1, 2 or 3 R d substituted by 1, 2 or 3 R substituted by 1, 2 or 3 R substituted by 1, 2 or 3 R substituted by 1, 2 or 3 R substituted by 1, 2 or 3 R substituted by 1, 2 or 3 R substituted by 1, 2 or 3 R substituted by 1, 2 or 3 R substituted by 1, 2 or 3 R substituted by 1 R c and R d independently deuterium; R 3 haloalkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C6-C10aryl, 5-10 membered heteroaryl, or 3-8 membered heterocycloalkyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocycloalkyl in R1is optionally substituted by 1, 2, 3, or 4 substituents independently selected from C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6haloalkyl, and C1-C6haloalkoxy; C6-C 10 haloalkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C6-C10aryl, 5-10 membered heteroaryl, or 3-8 membered heterocycloalkyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocycloalkyl in R1is optionally substituted by 1, 2, 3, or 4 substituents independently selected from C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6haloalkyl, and C1-C6haloalkoxy; R 3-1 is hydrogen, Ci-C6-alkyl, Ci-C6-alkoxy, C 3-6 cycloalkyl, "3-8 membered heterocycloalkyl, wherein 1, 2 or 3 heteroatoms are selected from N, O and S, and the number of heteroatoms is 1, 2 or 3" or -NR a R b ; R a and R b independently are hydrogen, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R 4 and R 5 independently hydrogen or deuterium; and the compound of Formula I meets one or more of the following conditions: (1) R 3 To (2) R 1 To (3) X is -CR 1-1 R 1-2 -; wherein R 1-1 and R 1-2 at least one of which is deuterium; (4) R 4 and R 5 at least one is deuterium; (5) R 2 C1-C6alkyl substituted by 1, 2, or 3 R d C1-C6alkoxy substituted by 1, 2, or 3 R 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula I, ###0001### I which meets one or more of the following conditions: (1) each of the C1-C6 alkyl and the C1-C6 alkyl of the substituted C1-C6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl; preferably ethyl; (2) each of the C3-C6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; preferably cyclopropyl; (3) each of the C1-C6 alkoxy and the C1-C6 alkoxy of the substituted C1-C6 alkoxy is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, or t-butoxy; preferably methoxy; (4) R 3 In some embodiments, the C1-C6haloalkyl is independently halomethyl, haloethyl, halogenormal-propyl, haloisopropyl, halogenormal-butyl, haloisobutyl, halogenesecond-butyl, or halo-tert-butyl; the halo is fluoro, chloro, bromo, or iodo; and (5) R 3 In particular, the C6-Ci8aryl group is a phenyl group. 10 The aromatic ring is a benzene ring or a naphthalene ring.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula I, ###0001### I which meets one or more of the following conditions: (1) R 1-1 and R 1-2 independently hydrogen; (2) R 2 C1-C6-alkyl or C1-C6-alkoxy; preferably C1-C6-alkyl; and d C1-C6-alkyl or C1-C6-alkoxy; preferably C1-C6-alkyl; and (3) R 3 C1-C6alkyl or (4) R 3-1 is C3-C6cycloalkyl or -NR a R b ; (5) R a and R b independently hydrogen; and (6) R 4 and R 5 is independently hydrogen.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula I, ###0002### I which meets one or more of the following conditions: (1) R 2 is methoxy or and (2) R 3 is ethyl, 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula I, ###0002### I which meets one or more of the following conditions: Scheme 1, X is -CR 1-1 R 1-2 -; R 1-1 and R 1-2 independently hydrogen or deuterium; Y is -CR 2-1 R 2-2 -; R 2-1 and R 2-2 is independently hydrogen; R 1 is hydrogen or R 2 C1-C6-alkyl or C1-C6-alkoxy; d C1-C6-alkyl or C1-C6-alkoxy; R 3 C1-C6alkyl or R 3-1 C3-C6cycloalkyl or -NR a R b ; R a and R b are independently hydrogen; R 4 and R 5 are independently hydrogen or deuterium; and the compound of Formula I meets one or more of the following conditions: (1) R 3 To (2) R 1 To (3) X is -CR 1-1 R 1-2 -; wherein R 1-1 and R 1-2 are each independently hydrogen or deuterium; (4) R 4 and R 5 are each independently hydrogen or deuterium; (5) R 2 C1-C6alkyl substituted by 1, 2, or 3 R d C1-C6alkoxy substituted by 1, 2, or 3 R Scheme 2, X is -CR 1-1 R 1-2 -; R 1-1 and R 1-2 is independently hydrogen; Y is -CR 2-1 R 2-2 -; R 2-1 and R 2-2 is independently hydrogen; R 1 is hydrogen or R 2 is Ci-C6-alkoxy; R 3 C1-C6alkyl or R 3-1 C3-C6-cycloalkyl or -NR a R b ; R a and R b is independently hydrogen; R 4 and R 5 is independently hydrogen; and the compound of Formula I meets one or more of the following conditions: (1) R 3 To and (2) R 1 To 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula I, ###0001### I the compound of Formula I is a compound of Formula I-1, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X and Y are as defined in any one of claims 1-5.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula I, ###0002### I the compound of Formula I is any one of the following structures, for example, 8. A compound of the following structure, and salts thereof, wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in any one of claims 1-5; For example, 9. A pharmaceutical composition comprising: (1) a compound of Formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, and (2) a pharmaceutically acceptable excipient.

10. Use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, a pharmaceutical composition according to claim 9, in the manufacture of a medicament for the treatment and / or prevention of a tumor and / or a selective estrogen receptor; the tumor can be breast cancer, for example, MCF-7 breast cancer.

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